Hepatitis C virus (HCV) infection is most often clinically inapparent and rarely associated with symptoms of acute hepatitis. Most patients, however, fail to resolve the acute infection and proceed to develop chronic hepatitis with the risk of liver cirrhosis and hepatocellular carcinoma later in life. Since the kinetics of virus-host interaction in the earliest phase of infection is the major determinant for the outcome of infection, we are interested in the analysis of the cellular immune response in the very early phase of hepatitis C virus infection. The identification of the immunological correlates of viral clearance is pivotal to developing vaccines and efficient therapies. Research thus far has been hampered by the fact that patients with well documented episodes of acute, self-limited hepatitis C are rare, that the intrahepatic immune responses at the site of inflammation cannot not be prospectively studied, and that sequences of the infecting virus are often unknown and rather heterogeneous. The recent identification and characterization of stable, infectious molecular clones provides the necessary tools to perform prospective analyses of the cellular immune response in chimpanzees after infection with defined HCV inoculates of a homogenous and well-characterized sequence. We have prospectively monitored the peripheral and intrahepatic proliferative T cell response to HCV over a period of six months in a chimpanzee that was successfully infected by intrahepatic inoculation with a cDNA clone of HCV genotype 1a. We have detected a multispecific proliferative T cell response targeted against all proteins of the hepatitis C virus in both the liver and the blood early after infection and generated HCV-specific T cell lines and clones that were characteized as CD4 positive, IFN gamma-secreting Th1 clones. Importantly, both the numbers as well as the proliferative rates of liver-derived T cells correlated with the rise of serum alanine aminotransferase activity in the blood. Experiments to determine the effects of this immune response on viral quasispecies distribution, disease pathogenesis and long-term outcome of infection are currently underway.